Overall Abstract Our overall goal is to translate new, small molecule drugs into personalized therapies for severe asthma and cystic fibrosis (CF). Severe asthma and CF are disabling obstructive lung diseases that have been a particular focus of our therapeutic development efforts. In our pediatric and internal medicine research programs, we have developed potentially effective small molecule therapies for both. In many cases, these therapies are similar or identical in both diseases. For example, S-nitrosoglutathione (GSNO), GSNO-mimetic compounds and GSNO reductase inhibitors are potentially active in both conditions. However, it is now clear from our work and that of others that there is substantial clinical heterogeneity in both severe asthma and CF, and that there are specific patients who will and will not respond to each treatment. As with most drugs, patients who are non-responders could actually be harmed by unnecessary treatment. We have now developed noninvasive or minimally invasive biomarker approaches to identify responders and non-responders to specific treatments. Therefore, we propose in the first phase of this program to use these novel techniques to identify patients who will and will not likely respond to our proposed therapies. We will study targets and mechanisms of action for these therapies, including biochemical and epigenetic effects. We will also use these data to inform studies of interactions between therapies in vitro and in vivo. In the second cycle, we will begin personalized clinical trials using specific clinical testing and selection criteria developed in the first cycle. Many severe asthma and CF patients are benefitting already from personalized biological and small molecule therapies that have recently been developed; our proposed program is meant to complement these novel therapies in order to optimize the ease and efficacy ? and minimize the cost - of treatment for each patient. Our multidisciplinary program is based strengths in drug development, clinical drug trials, airway redox chemistry, cell culture, cell physiology and genetics as they relate both to severe asthma and to CF.